Updates on C. difficile: from clinical trials and guidelines – an interview with Yoav Golan

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In this interview, we spoke to Yoav Golan, an Attending Physician and Associate Professor of Medicine at Tufts University School of Medicine (MA, USA), about recent developments in the field of Clostridium difficile infections. From the latest clinical trial results to newly updated guidelines, you can find out more in the interview below.

First, could you introduce yourself and tell us a bit more about your background?

I’m a physician specializing in adult infectious diseases. I practice in a university hospital in the city of Boston (MA, USA) where I split my time between patient care and research. My main research interest is infections acquired in hospitals; over the past 10 years I’ve focused on infections with C. difficile and I also work on new antibiotic development.

One recent development in the field is the SUNSHINE study, could you tell us a bit more about this study and the rationale behind it?

As a general comment I would first say that the way we care for C. difficile doesn’t make sense – it’s an antibiotic-related complication and we treat it with an antibiotic – we use the risk factor for developing the infection to actually treat the infection!

For a while now we’ve been looking for other solutions, one of which is using antibiotics that are very narrow-spectrum, tailored, or would target Clostridium but not most of the other bacteria in the gut. For the past 10 years we’ve had this available in the form of fidaxomicin; however, there hasn’t been any data available for pediatrics.

With increasing incidence of C. difficile in children there was obviously a need to look at better treatment options for children, not just for adults. When you look at C. difficile, whether in adults or children, it can cause very severe disease in both age groups and one of the main unmet needs with C. difficile has been the very high recurrence rate. Many would argue, including myself, that a big proportion of those who have recurrence recur because we treat their initial C. difficile episode with broad-spectrum antibiotics. If we treat the condition with antibiotics we’ve produced the risk factor for the next episode and so we have to change our ways in both adults and in pediatrics.

So that was the background of this study. In fact, this study has been long overdue. Since the approval of fidaxomicin [in 2011]this study has been needed and many have been asking for this data.

Could you outline the key results and the implications these might have on patients’ lives?

The SUNSHINE study, in which I was not involved, was unlike other studies with C. difficile in that it enrolled children younger than 18. The study enrolled 142 children who were stratified by their age group and randomized (2:1) to receive either fidaxomicin or vancomycin. These children all had an episode of C. difficile and for some of the children this was not the first episode of C. difficile but a recurrent episode.

All the participants were evaluated for cure of their symptoms and for persistence of this cure (or global cure) – which means being cured and not having a recurrent episode within the follow-up period. The results of the study show that the cure rate for the fidaxomicin arm was 77.6% vs 70.5% for vancomycin arm, with a percentage difference of 7.5% in favor of fidaxomicin. Moreover, if you looked at the likelihood of recurrence in those who were cured it was 11.8% among fidaxomicin-treated children and 29% among vancomycin-treated children with an absolute reduction of recurrence of 15.8% in favor of fidaxomicin.

Finally, if you look at global cure, this was seen in 68% of fidaxomicin-treated patients and 50% of vancomycin-treated patients.

The importance of the study is that we now know that fidaxomicin is safe in children, including very young children and babies. We know how to dose it and we know that fidaxomicin works well in this population. The differential effect in favor of fidaxomicin vs vancomycin in children is very similar to what we’ve seen in adults with regards to cutting recurrence – in adults we see a relative decrease in recurrence by about 50%; in children, we actually see a greater decrease in recurrence. The study results are encouraging and really establish, in my eyes, fidaxomicin as a new treatment option for children, particularly children who are at risk for recurrence of C. difficile.

Looking at C. difficile more broadly, there’ve been some recent updates to the IDSA guidelines; could you outline some of the major changes for us?

There are different organizations releasing different guidelines – the IDSA’s are the most recently published and probably the most followed guidelines. There are a few changes in the recent update. The first notable change is in classification. The guidelines have always guided clinicians to treat C. difficile by severity, but how you define severity has changed a little bit – with the more severe presentation of cases this used to be called severe-complicated C. difficile and now it’s called fulminant C. difficile – so that’s one change.

Another of the major changes is the removal of the recommendation to use metronidazole as first-line treatment for patients with mild and moderate C. difficile. Metronidazole is a very broad-spectrum antibiotic that has an immense depleting effect on the gut flora and causes severe damage; some data suggests the recurrence rate with metronidazole may actually be higher than it is with other agents.

The recommendation is now to only use metronidazole if the patient really doesn’t have any access to vancomycin or fidaxomicin. This is an important change because many patients with C. difficile, perhaps even most of the patients around the world, receive metronidazole.

The other major change in the guidelines is the incorporation of fidaxomicin and the recommendation to use fidaxomicin for treatment, regardless of severity of disease and regardless of whether it is the first episode or a recurrent episode. Fidaxomicin was approved after the last version of the IDSA/SHEA guidelines was published, thus it was not included in the guidelines. I believe that there’s no question that fidaxomicin is the most effective treatment for C. difficile – particularly from the perspective of sustaining the response or preventing recurrence.

Fecal transplant has also been included in the guidelines for the first time, could you comment on that and the potential you think that might have as a treatment?

Fecal transplant has many different names but it basically refers to using feces obtained from an individual donor or donor bank, and giving it to a person who has experienced several episodes of C. difficile infection in order to prevent additional recurrences. It can be given in the form of capsules or through a naso-gastric tube or colonoscopy.

It’s a costly procedure because you have to test the donor’s feces for pathogens, perform a costly colonoscopy or purchase the feces capsules. Moreover, it’s potentially hazardous. Although we screen the feces for some pathogens, other pathogens may still exist in the donated feces as well as other risk factors in the microbiome linked to other diseases that currently we don’t quite understand.

Fecal transplants work very well and the likelihood of recurrent episode of C. difficile after a fecal transplant is relatively low. Fecal transplants have been mostly studied in people with multiple recurrences so it’s only really been offered to a small slice of the overall population with C. difficile.

It’s an effective procedure and probably will continue to be offered for quite a few years until we find the vital components of the fecal transplant that could be given without all the other content of the feces – then it will become a little more elegant and cost-effective as well as less risky.

However, the approach that I believe is becoming more mainstream, is to do whatever you can do upfront to prevent the first recurrence thus avoiding a situation with multiple recurrences and becoming a candidate for fecal transplant.

What challenges do you think are still facing the field?

There are several different challenges. One is that over the past 30 years we only had one antibiotic approved for the treatment of C. difficile, which is fidaxomicin, and it would be helpful to have additional antibiotics.

Another challenge is people with multiple recurrences, as discussed; we need to find better approaches and safer approaches for these individuals. The third challenge is patients who present with very severe disease, what is now defined as fulminant disease; we haven’t had any randomized clinical trials enrolling these patients and no new treatment options for them have been developed.

The final challenge is the higher cost of new agents that come to the market. As, newer antibiotics are always more costly to acquire, it is important that we improve our understanding of the tradeoffs in caring for patients with C. difficile infections.  This starts with the appreciation of the burden of C. difficile, the mortality, morbidity and cost of care associated with managing these patients, and the potential to see cost reductions with effective prevention of C. difficile recurrence.  Unfortunately, many clinicians under value interventions to reduce recurrence and underutilize such interventions to the benefit of their patients.

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